Articular cartilage covers bone surfaces in diarthrodial joints and is composed of cartilage matrices and a small amount of chondrocytes. Articular cartilage has little blood flow, and thus it is usually said that articular cartilage, once degenerated or lost, can hardly be repaired. Diseases associated with loss or degeneration of articular cartilage are, for example, traumatic chondropathy, rheumatoid arthritis, osteoarthritis, etc. In addition, articular cartilage thins with aging.
Osteoarthritis is a progressive degenerative arthritis characterized by articular cartilage degeneration, and subchondral bone growth and remodeling. The disease presents with symptoms such as stiffness, movement limitation and pain, and increases in incidence with age. However, there is no treatment for radical cure of osteoarthritis because cartilage has a limited self renewal capacity, and the current treatment of osteoarthritis is to control pain by exercise restriction and painkiller medication. In the case where the disease has progressed into the terminal phase, joint arthroplasty, which is a surgery involving excising degenerated articular cartilage and resurfacing the bone with a metal cover, is a treatment option.
For the development of cartilage repair promoting agents, screening for compounds and proteins promoting chondrocyte growth has been carried out, and SIK3-inhibiting compounds have been reported to be a candidate (Patent Literature 1). Further, bone morphogenetic proteins (BMPs) are known to be capable of actually promoting cartilage growth at the tissue level. However, BMPs, after inducing cartilage growth, induce hypertrophic differentiation of chondrocytes, resulting in the replacement of cartilage by bone. Due to the action, it is problematic to use BMPs for the treatment of articular cartilage defects. In recent years, it has been suggested that promotion of chondrocyte hypertrophy is involved in articular cartilage degeneration, and preventing chondrocyte hypertrophy is a major therapeutic target for osteoarthritis. The target molecules identified so far include Hedgehog (Non Patent Literature 1) and Hif-2α (Non Patent Literature 2 and 3). It is also reported that transient activation of β-catenin signaling induces articular cartilage thickening (Non Patent Literature 4).
For the treatment of articular cartilage injuries and growth cartilage injuries caused by trauma, blood circulation failure, etc., regenerative medicine using transplantation of stem cell-derived cells has been studied. However, chondrocyte-like cells derived from stem cells tend to undergo hypertrophy, which poses a problem (Non Patent Literature 5).